Certain synthetic bisphosphonate compounds having a methanebisphosphonic acid structure which are structurally analogous to pyrophosphoric acid and stable also in vivo (hereinafter referred to as bisphosphonic acid derivatives or pharmaceutically acceptable salts thereof, or sometimes merely as bisphosphonic acid derivatives) have biological actions such as an excellent bone resorption inhibitory action, ectopic calcification inhibitory action, etc. and are useful as agents for the treatment of diseases associated with accelerated bone resorption, ectopic calcification, etc., e.g., osteoporosis, Paget's disease of bone, hypercalcemia accompanied by malignant tumor, etc. Some of them have already been used clinically.
As bisphosphonates commercially available so far and currently under development, there are known alendronate, ibandronate, incadronate, etidronate, olpadronate, clodronate, zoledronate, tiludronate, neridronate, pamidronate, risendronate, minodronic acid [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidenebisphosphonic acid], disodium 1-hydroxy-3-(1-pyrrolidinyl)propylidenebisphosphonate, etc.
In particular, incadronic acid or minodronic acid or pharmaceutically acceptable salts thereof including incadronate (disodium incadronate) or minodronic acid have a potent bone resorption inhibitory action, an excellent anti-inflammatory action and antipyretic analgesic action, and are useful for diseases such as hypercalcemia, etc., caused by bone resorption (JP-B-6-99457 and JP-B-7-629).
Pharmacokinetic studies on tiludronate, pamidronate, etidronate, clodronate and alendronate have been extensively made. It is reported that these bisphosphonates are poor in bioavailability when orally administered, should avoid alimentary effects since their absorption is suppressed especially in the presence of calcium or iron, deposit very rapidly onto bone and might cause gastrointestinal disorders by oral administration though they are mild, and further that recent studies revealed bioavailability of the bisphosphonates even when administered pernasally or percutaneously, and so on (see “Bisphosphonates and Bone Disease: Kiso-to-Rinsho (The Clinical Report)” Jul. 30, 1996, published by Ishiyaku Publishers Inc.).
On the other hand, British Patent No. 1,582,694 discloses a composition suitable particularly for topically treating the anomalous mobilization and deposition of calcium phosphate salts in the tissues of humans and lower animals, including percutaneous administration, which comprises a safe and effective amount of an organophosphonate compound in combination with a carrier containing a safe and effective amount of an organosulfoxide compound as a specific penetration enhancer. Particularly in the patent supra, a composition composed of etidronate or clodronate, decyl methyl sulfoxide, water, or a cream base penetrating carrier composed of water, ethanol, stearyl alcohol and lanolin is shown as a specific example of formulations. It is described in the patent that a typical organosulfoxide compound, decyl methyl sulfoxide, enhanced especially in the skin permeation test in vitro by about 6-fold the penetration effect of etidronate, which is a typical example of the organophosphonates, as compared to control; in the in vivo tests with rats to verify therapeutic effects on dihydrotachysterol-induced calcification (calciphylaxis), a skin calcium level (%) was 0.035 in the normal control and 0.067 in the control with etidronate alone dissolved in the penetrating carrier vehicle, whereas the skin calcium level was enhanced to 2.026 when treated with a composition composed of etidronate and a penetrating carrier containing decyl methyl sulfoxide.
U.S. Pat. No. 5,133,972 also discloses a pharmaceutical preparation for topical application, which comprises a particular methanediphosphonic acid represented by formula (I) below:
(wherein . . . Het1 is unsubstituted or substituted, monocyclic, 5- or 6-membered monoaza-, diaza- or thiaza-aryl that is bonded via a ring carbon atom, or R1 is . . . hydroxy group, R2 is -A-R3, in which A is an alkylene group and, on the one hand, R3 is Het2, which is Het1 bonded via a ring carbon or ring nitrogen atom, or, . . . ) (As to further detailed definitions, please see the above-mentioned U.S. Patent specification) or pharmaceutically acceptable salts thereof. According to the above-mentioned Specification, it is described that “it was discovered that pharmaceutically acceptable methanebisphosphonic acids, especially those of formula I below, are readily conveyed through the skin and can thus immediately act systemically,” indicating that these unexpected discoveries were made during the particular studies in vitro. Though the test method is described in detail, any data concerning percutaneous permeability is not disclosed at all. The above-mentioned Specification merely describes various formulations of zoledronate specifically.
Incadronic acid, the chemical structure of which is characterized in binding its cycloheptane ring at the 1-position not via a lower alkylene group, or pharmaceutically acceptable salts thereof and the said minodronic acid, the chemical structure of which is characterized in having the imidazopyridine ring which is not a monocyclic hetero-ring but a bicyclic hetero-ring, or pharmaceutically acceptable salts thereof are not included in the chemical formula I described in the U.S. patent.
Thus, any specific percutaneous preparation which contains as the effective ingredient incadronic acid or minodronic acid, or pharmaceutically acceptable salts thereof is unknown so far.
In these bisphosphonates, pamidronate or the like is made available as an oral preparation. However, the bisphosphonates are poor in absorbability per os and sometimes cause an undesired effect such as gastrointestinal disorders, etc. when a large dose is administered. In practice, the bisphosphonates are administered as injections. In the form of injections, pain is attendant and patients' compliance is lowered where prolonged administration is required. Especially, a bisphosphonate having a weak effect is often administered continuously over a prolonged period of time. Under these situations, a great demand still exists to develop a preparation with a minimized burden on the patient without deteriorating patients' compliance even when administered over a long period of time. It is also earnestly desired to develop a preparation capable of achieving therapeutic effects in a short period of time.